December 20th 2022

Published in Structure: An insight into nsp10-mediated modulation of nsp14 exonuclease activity

Published in Structure: An insight into nsp10-mediated modulation of nsp14 exonuclease activity

The CARE partners Jagiellonian University (JU, Poland) and the Universty of Dundee (UnivDun, UK) discovered a key component of the regulation of nsp14 exonuclease activity by nsp10 using X-ray crystallography.

During RNA replication, coronaviruses require proofreading to maintain the integrity of their large genomes. This is a role of the SARS-CoV-2 nonstructural protein nsp14, which associates with viral polymerase complex to excise the mismatched nucleotides. The nsp14 exonuclease activity is modulated by a protein co-factor nsp10, which binds to nsp14.

Although the nsp10/nsp14 complex structure was already available, the mechanistic basis for nsp10-mediated modulation remains unclear. This is now solved thank to Czarna et al who provide the crystal structure of nsp14 in an apo-form, i.e., the structure of nsp14 alone.

The comparison of the nsp14/nsp10 structure with the nsp14 structure led to the discovery that the N-terminal region of nsp14 acts as a lid, covering the nsp10 binding site in the absence of the protein co-factor. The lid rearranges its structure in the presence of nsp10 to create a significant interaction surface with nsp10.

Nsp14 being a valid target in SARS-CoV-2 fight, by revealing the allosteric nsp14 control mechanism and offering crystallization conditions suitable for soaking of small molecules, this study provides essential information that will facilitate the effort in the development of an anti-coronaviral drug.

To learn more, click here: Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity.